1. Field of the Invention
The present invention relates to an amorphous cefditoren pivoxil composition, which is highly stable and has improved dissolvability, a pharmaceutical composition for oral administration comprising said amorphous composition, and a process for producing the same.
2. Background Art
Cefditoren pivoxil is a novel prodrug in which a pivaloyloxymethyl group has been attached by an ester bond to a carboxylic acid at the 4-position of an antibiotic cefditoren having a wide antimicrobial spectrum, namely (+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, known also in the chemical name of [6R-[3(Z),6α,7β(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, for the purpose of imparting excellent oral absorption to cefditoren. Cefditoren pivoxil is represented by formula (I):
Further, cefditoren pivoxil is known in the name of (−)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester. Another chemical name of this compound is [6R-[3(Z),6α,7β(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid (2,2-dimethyl-1-oxopropoxy)methyl ester).
It is generally known that cefditoren pivoxil, when used as an oral preparation, has a very broad antimicrobial spectrum while enjoying low toxicity and is very useful for the therapy and prophylaxis of diseases induced by gram-positive and gram-negative bacteria (see, for example, Japanese Patent Publication No. 64503/1991, U.S. Pat. No. 4,839,350, and European Patent No. 175610).
Crystals of cefditoren pivoxil are known to have high purity, high heat stability, and, in addition, satisfactory stability even when stored under high humidity conditions (see WO 98/12200 and U.S. Pat. No. 6,294,669).
Crystals of cefditoren pivoxil, however, have low solubility in water and thus have not been very suitable for oral administration of cefditoren pivoxil per se.
In general, in medicinal compounds sparingly soluble in water, the solubility or dissolution rate thereof is known to greatly affect the absorption of these compounds in vivo. Accordingly, many reports about how to improve the dissolvability of the medicinal compounds sparingly soluble in water were presented.
An example of these methods is to convert a medicinal compound to an amorphous substance having improved dissolvability which is then utilized as preparations. Amorphous substances are generally known to have smaller energy necessary for dissolution, that is, a higher level of dissolvability, than the corresponding crystalline substances.
Therefore, the conversion of a crystalline form of cefditoren pivoxil sparingly soluble in water to an amorphous substance having high water solubility leads to the expectation of improved usefulness of cefditoren pivoxil in the therapy of diseases.
An example of a method for converting the crystalline form of cefditoren pivoxil sparingly soluble in water to an amorphous substance having high water solubility is described in WO 99/34832 and U.S. Pat. No. 6,342,493. In this method, the crystalline cefditoren pivoxil is dissolved in an acidic aqueous solution containing a water-soluble polymeric additive, the acidic aqueous solution is then neutralized to coprecipitate cefditoren pivoxil together with the water-soluble polymeric additive, and the precipitate is then collected, washed, and dried. According to this method, a yellow-colored powdery composition comprising solid particles of an intimate mixture of an amorphous form of cefditoren pivoxil having a high level of dissolvability in water and high heat stability with the water-soluble polymeric additive (0.5 to 5%) can be provided.
This method, however, involves many steps and thus requires process control and a relatively lot of time. Therefore, the above method is not necessarily satisfactory from the viewpoint of production efficiency.
Thus, a composition of an amorphous form of cefditoren pivoxil having a combination of stability and dissolvability, which are desired in orally administrable pharmaceutical compositions, is desired.